Dietary supplement composition for blood lipid health

ABSTRACT

A method for enhancing gastrointestinal motility in humans and other mammals comprises administering a therapeutically effective amount of a composition having one or more long chain (C24-C36) primary alcohols as policosanols dispersed in one or more food-grade fats or oils, wherein the particle sizes of the alcohols are substantially less than 10 microns.

RELATED APPLICATIONS

This application is a divisional of Ser. No. 12/336,560 filed Dec. 17, 2008, which is a continuation-in-part application of Ser. No. 11/671,757 filed Feb. 6, 2007, which is based on provisional application Ser. No. 60/771,003 filed Feb. 7, 2006, the disclosures of which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to dietary supplements, and, more particularly to the formulation of such supplements containing fatty alcohols.

BACKGROUND OF THE INVENTION

Cholesterol is an essential component in the body and used in cell membranes. Excessive levels, however, can lead to hypercholesterolemia and atherosclerosis, which can result in coronary heart disease. Cholesterol is transported via: high-, low-, intermediate-, and very low-density lipoproteins; chylomicron remants; and chylomicrons. High levels of high-density lipoproteins are desirable because they transport cholesterol from the peripheral tissues to the liver, thereby maintaining cholesterol homeostasis. The main transport mechanism, however, is low-density lipoprotein, which moves cholesterol in the blood plasma and incorporates it into cell membranes. Increased levels of low-density lipoprotein, however, can interfere with uptake binding mechanisms.

Statin drugs such as atorvastatin, fluvastatin, pravastatin and simvastatin are often administered to those suffering from cholesterol issues. These drugs inhibit competitively 3-hydroxy-3-methylglutaryl coenzyme A reductase, thereby reducing cholesterol synthesis. Side effects of statins can include myositis, headache, rash, angioedema, gastrointestinal effects and altered liver functions. In addition, these drugs should not be used in patients with renal failure or in people with compromised liver function (Taylor et al. 2003).

Dietary fatty acid intake can influence many health factors, but much interest has been placed on the n-3 (omega-3) fatty acids. These essential fatty acids include α-linolenic (ALA), eicosapentaenoic (EPA) and docosahexaenoic acid (DHA). Various studies have shown that n-3 fatty acids are essential for normal growth and development. They may also play a critical role in the prevention and treatment of coronary heart disease, hypertension, diabetes and other inflammatory and autoimmune disorders (Simopoulos 1999). ALA is present in certain vegetable oils (flaxseed, cranberry seed, canola and chia) whereas EPA and DHA are found in fish, fish oil and algae products.

Between ethnic dietary groups it has been shown that the higher ratio of n-6 to n-3 in thrombocyte phospholipids can be a cause for a higher death rate from cardiovascular disease. This increased ratio also results in increased rates of type 2 diabetes, of which atherosclerosis is a major complication (Weber, 1991). Achieving target levels of n-3 fatty acids can be difficult with modern western diets deficient in ALA, EPA and DHA, and excessive in the n-6 linoleic acid. Target tissue concentrations for ALA and EPA can be met with consumption of ALA (Mantzioris et al. 2000). A primary cardiovascular benefit from n-3 fatty acid ingestion can be reduced blood clotting in vessel walls and reduced ventricular arrhythmias, (Zhao et al. (2004)). Some studies have found a dose-response relation between n-3 intake and beneficial effects on cardiovascular disease risk factors. Some studies have shown an inverse relationship between ALA intake and risk of sudden cardiac death (Albert et al. (2005)).

Policosanols can be defined as a mixture of long chain (C24-C36) aliphatic primary alcohols, which are commonly derived from sugar cane, rice bran, beeswax, wheat or sorghum. Predominant alcohols in this group are tetracosanol, hexacosanol, octacosanol and triacontanol.

Policosanols can lower cholesterol levels by inhibiting cholesterol biosynthesis via downregulation of 3-hydroxy-3-methylglutaryl Coenzyme A enzyme expression (Menendez et al. 1994, McCarty 2002). A study by Hernandez et al. (1992) found a reduction in serum cholesterol levels of subjects taking 20 mg policosanol per day for 4 weeks. Significant decreases in LDL levels, with increased levels of HDL were also noticed. Another double-blind randomized study by Castano, et al. (1999) investigated the effects of policosanol and pravastatin on the lipid profile in older hypercholesterelemic patients. Policosanol was found to increase HDL levels, but was also more effective than pravastatin in lowering LDL levels and the LDL:HDL ratio.

Policosanols can also protect lipoproteins from peroxidation, in both lipid and protein moieties (Menendez et al. 1999). This can be an important effect, since LDL oxidation is thought to be a necessary step in the development of atherosclerosis.

Policocanols may provide fewer side effects than statins, increase HDL cholesterol levels and have a reduced cost (Taylor et al. 2003).

One issue with policosanols are poor solubility, and difficulty with absorbtion in the gut. Human studies with [³H]-octacosanol showed the majority (81-91%) of total radioactivity was excredted in the feces, and only 1.2% of total radioactivity was found in urine (Mas, 2000).

Reducing parent the particle size of poorly solube compounds such as policosanol to a micron or sub-micron range, improved absorbtion and bioavailabilty is desirable.

Copending parent application Ser. No. 11/671,757 filed Feb. 7, 2006, discloses a human or animal dietary supplement composition that comprises a blood lipid health-effective amount of one or more long chain (C24-C36) primary alcohols (policosanols) dispersed in one or more food-grade fats or oils, wherein the particle sizes of the alcohols are substantially less than 10 microns.

SUMMARY OF THE INVENTION

During trials, it was found that positive and advantageous results further included reductions in base level for AST and ALT and an increase in the AST/ALT ratio. Also, there was a reduction in gastrointestinal esophageal reflux disease (GERD) symptoms and a reduction of irritable bowel syndrome symptoms.

In accordance with a non-limiting aspect, the method enhances gastrointestinal motility in humans and other mammals. The method comprises administering a therapeutically effective amount of a composition having one or more long chain (C24-C36) primary alcohols as policosanols dispersed in one or more food-grade fats or oils, wherein the particle sizes of the alcohols are substantially less than 10 microns.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Different embodiments will now be described more fully hereinafter with reference to the accompanying drawings, in which preferred embodiments are shown. Many different forms can be set forth and described embodiments should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope to those skilled in the art.

The natural dietary supplement industry represents a $300 billion dollar marketplace worldwide. Many natural botanical materials and extracts have been used by mankind for health purposes for thousands of years. In some parts of the world, natural health products are preferred over chemical or pharmaceutical ones due to reasons of religion, culture, safety, cost and demonstrated efficacy.

Among the botanical products that have a history of use in support of human blood lipid health are certain fatty alcohols derived from botanical waxes, for example, sugar cane wax, rice bran and other cereal waxes and bees wax. The most important of these are the long chain (C24-C36) primary alcohols, octacosanol, triacontanol and hexacosanol.

Policosanols, as noted above, are known to have a number of beneficial effects on blood lipid health. These beneficial effects include lowering blood cholesterol levels, reducing Low Density Lipoproteins (LDL), increasing High Density Lipoproteins (HDL) and reducing blood triglycerides.

Some difficulties have been experienced in using policosanols to improve blood lipid health. For example, these fatty alcohols are poorly soluble in lipid carriers and completely insoluble in aqueous carriers. This greatly reduces their availability in the digestive tract. Normal digestion of fats and oils in the mammalian diet is achieved by emulsification with bile salts and phospholipids followed by direct adsorption of the resulting chylomicrons through the gut wall. Typical chylomicron sizes are 0.5 microns to 2 microns.

Modern emulsification technology (nanotechnology) now makes it possible to produce dispersed particle sizes in liquid carriers into the 1 micron size. As noted above, many different physical emulsification techniques are available.

In accordance with a non-limiting example of the present invention, one or more of these technologies is used to prepare a dietary supplement composition in which the policosanol particle sizes are substantially less than 10 micron range within an acceptable oil carrier (Nanocosanol™). The composition may include the use of food-grade emulsifiers, for example, polysorbates, lecithin, hydrolyzed lecithin, mono- and di-glycerides, and acylated mono- and di-glycerides. The presence of the emulsifiers inhibits the tendency of the particles to adhere under electrostatic attractive forces. Such a composition has the advantage of increased digestability and stability on storage.

In one aspect, the composition includes the selection of an oil carrier with beneficial blood lipid properties. Such fats and oils may include polyunsaturated fatty acids, omega-3 fatty acids, squalene, phytosterols, tocopherols and tocotrienols. Typical fats and oils include, for example, fish oils, shark liver oil, cranberry seed oil, amaranth seed oil, sunflower seed oil, linseed oil, chin oil and evening primrose seed oil.

In another aspect, the composition optimizes the balanced intake of both policosanols and the beneficial lipid carrier. By suitable selection of the ratio of the carrier oil to the policosanols, it is possible to produce the composition such that preferred intakes of both policosanols and the beneficial lipid can be conveniently administered in acceptable unit and daily doses.

Such a composition as (Nanocosanol™) can be used to promote and support blood lipid health. Daily intake of such composition, in the preferred dose range, will provide the subject with the desired daily intakes of policosanols and lipid carrier, resulting in improved blood lipid profiles. This can include, for example, lower cholesterol, lower triglycerides, lower Low Density Lipoprotein (LDL) and higher High Density Lipoprotein (HDL).

In accordance with one aspect of the present invention, a dietary supplement composition is disclosed (Nanocosanol™) in which poorly soluble policosanols are dispersed in food-grade oils or fats, in which the policosanol particle sizes in the composition are substantially less than 10 microns and preferably in the range of from about 0.2 microns to about 5.0 microns.

In accordance with another aspect of the present invention, the body's absorption and utilization of the policosanols from the composition is substantially enhanced as compared with the absorption and utilization of policosanols administered in solid or tablet form. The policosanol dispersion of the composition is stable on storage and does not separate from the lipid carrier.

The disclosed lipid carrier used in the composition may be selected from a group of oils and or fats that are known to have beneficial effects on blood lipid health. Such beneficial lipids, for example, may contain one or more of polyunsaturated fatty acids, phytosterols, omega-3 fatty acids, squalene, tocopherols and tocotrienols.

The concentration of policosanols of the composition optimizes the daily intake of both policosanols and the beneficial lipid carrier. The preferred daily intake of policosanols can be about 20-30 mg per day for an adult. The preferred daily intake for beneficial lipids, however, is often as high as from about 500 mg to 5,000 mg per day for an adult. The weight of policosanols in the disclosed composition is from about 0.3 percent by weight of beneficial lipid to about 5.0 percent by weight of beneficial lipid. Such a disclosed composition allows the ratio of beneficial lipid to policosanols to range from about 333:1 to about 20:1. This ratio ensures that a policosanol intake of about 25 mg per day is always in combination with from about 500 mg per day to about 5,000 mg per day of the beneficial lipid. The disclosed composition allows delivery of a preferred daily dose of both policosanols and beneficial lipid in a single formulation.

It will be understood by those in the art that liquid dietary supplement daily doses of from about 500 mg to about 5,000 mg can be conveniently delivered in capsules from about 500 mg to about 1,000 mg. For example, a three percent dispersion of policosanols in a beneficial lipid can conveniently supply 24 mg of policosanols per day together with 800 mg of beneficial lipid, when taken as two 400 mg capsules daily.

It will be understood by those in the art that such a composition, in capsule or liquid form, may be conveniently supplemented with other biologically active extracts and compounds, including, for example, vitamins, minerals, antioxidants, carotenoids, tocopherols, tocotrienols, phytosterols, fatty alcohols, polysaccharides and bioflavonoids.

The disclosed dietary supplement composition (Nanocosanol™) is a novel, improved, more efficient vehicle for the administration of policosanols in support of blood lipid health. It is effective in lowering the blood serum cholesterol level of both normal and hypercholesterolemic subjects.

The following examples are illustrative of the present invention, and are not to be construed as limiting thereof.

EXAMPLE 1

Supercritical CO₂ Extracts of Cranberry (Vaccinium macrocarpon) Seed, Amaranth (Amaranthus hypochondriacus) Seed and Rice (Oryza sativa) bran wax were individually manufactured in a commercial 150 liter extraction unit. Within a heated vessel, the policosanol containing rice bran wax extract was dissolved into a mixture of cranberry and amaranth seed oily extracts at 65° C. After cooling to ambient temperature, soybean lecithin was combined. This resultant formulation was processed in a high pressure homogenization unit to obtain a stable dispersion of rice bran wax. The homogenizer is designed to produce high rates of shear and cavitation. Using light microscopy, average particle size was determined. Composition of the dispersion was as follows:

-   -   Policosanols: 1.45%, average particle size 0.3-2.6 μm.     -   alpha-Linolenic acid: 13.2%     -   Squalene: 3%     -   Tocopherols: 499 μg/g     -   Tocotrienols: 709 μg/g     -   Phytosterols: 4.4 mg/g

EXAMPLE 2

The Nanocosanol formulation from Example 1 was encapsulated in standard gelatin softgels by a third party manufacturer. Softgels were 690 mg nominal fill weight and each contained 10 mg policosanol, 21 mg squalene, 91 mg n-3 fatty acids (alpha-linolenic), 3.0 mg phytosterols, 489 μg tocotrienols and 344 μg tocopherols.

EXAMPLE 3

Nanocosanol™ softgels, manufactured according to Example 2 were administered to 11 subjects over an approximately 3-month period. The study was a non-placebo controlled open label trial and used volunteers with normal and modestly elevated levels of serum cholesterol. Starting point individual cholesterol levels ranged from about 140 to about 258. Dosage was 2×600 mg capsules per day providing 20 mg per day of policosanols together with 1200 mg per day of a 50:50 mixture of Cranberry and Amaranth Seed oils. In addition to the Policosonols, the Nanocosanol™ formulation provided tocopherols, tocotrienols, omega-6 and omega-3 fatty acids, polyunsaturated fatty acids and squalene.

Subject blood samples were taken by an independent clinic at 0 (Base), 30, 60 and 90 days. The blood samples were subjected to Blood Lipid by an authorized independent laboratory.

Variables measured were Triglycerides, Cholesterol, LDL Cholesterol and HDL Cholesterol.

All data were expressed as a difference (change) from the Base level for that subject and that variable. One subject did not complete a blood sample at 90 days so the total number of observations was 32 (11, 11, 10). Analyses were based the combined data over all three periods. The mean changes for the Blood Lipid variables were:

Triglycerides −4.72% p = 0.175 LDL Chol. −10.06% p = 0.125 HDL Chol. +1.85% p = 0.175 OTHER Chol. −5.23% p = 0.125 Chol. −5.96% p = 0.050 LDL/HDL −11.73% p = 0.050 Chol/HDL −7.43% p = 0.050

The Cholesterol reduction of 5.96% was significant at the 5% level of probability using the One-Sided t-test with 31 DF, as were the LDL/HDL ratio and the Chol/HDL ratio. The other Blood Lipid decreases are not significant at the 5% Level but have only a 1 in 6 to about 1 in 8 chance of occurring by chance.

The mean changes for the blood liver variables were:

AST −7.06% p = 0.050 ALT −13.78% p = 0.050 AST/ALT +7.39% p = 0.050

AST and ALT in the combined data were both significantly reduced at the 5% level of probability using the Two-Sided t-test with 31 DF. The AST/ALT ratio was significantly increased at the 5% level, as a result of ALT showing the greater reduction.

Analysis of Covariance was used to estimate the linear regression of variable change on variable Base level. The analyses tested the within-period regressions, differences between them, the pooled within period regression, the regression-adjusted means and the overall regression. Both the pooled within period regression coefficient and the overall regression coefficient for most variables were negative, highly significant at the 1% level (1 and 30 DF) and virtually identical.

Within period analyses for the Blood Lipid variables showed at least one period gave a significant regression of change on Base level at the 5% level with 1 and 9 DF. For all such variables except HDL the regression coefficients were negative in each period. For HDL the regression coefficients were positive in all three periods.

Within period analyses of the Blood Liver Variables showed consistent negative regression coefficients for AST and ALT although none were statistically significant.

All variables showed no evidence of within period differences between the regression coefficients or between the regression adjusted means. This would be expected given that the Base levels were identical for each period.

Both the pooled within period regression coefficient and the overall regression coefficient for most variables were negative, highly significant at the 1% level (1 and 30 DF) and virtually identical. The exceptions were HDL and AST/ALT.

Using the estimated regression equation, an estimate of the variable reduction resulting from a “typical high-quartile” Base level was calculated for each variable. These are shown as follows. No attempt was made to put Standard Errors on the estimates.

Triglyceride b = −0.2918 p < 0.010 Base = 200 Chng = −29.92 (−14.62%) LDL b = −0.8234 p < 0.010 Base = 150 Chng = −34.34 (−22.89%) HDL b = +0.0854 p = 0.175 OTHER Chol b = −0.2870 p < 0.010 Base = 35 Chng = −4.43 (−12.66%) Chol b = −0.7704 p < 0.010 Base = 225 Chng = −24.27 (−10.78%) LDL/HDL b = −0.4534 p < 0.010 Base = 2.75 Chng = −0.52 (−18.89%) Chol/HDL b = −0.3577 p < 0.010 Base = 5.00 Chng = −0.78 (−15.52%) AST b = −0.5720 p < 0.010 Base = 25 Chng = −4.32 (−17.27%) ALT b = −0.3554 p < 0.010 Base = 25 Chng = −4.20 (−16.75%) AST/ALT b = −0.0661 N.S.

The treatment resulted in significant and near significant reductions over base level for all Blood Lipid variables except HDL which showed a small increase. This slight increase in HDL should be seen as being a positive result. Nanocosanol was clearly and demonstrably responsible for a significant improvement in blood lipid health. This is most clearly established for Total Cholesterol and the critical LDL/HDL and Chol/HDL ratios. It is also likely that in a larger sample size, the reductions in Triglycerides and LDL and the increase in HDL, both desirable treatment effects, could be confirmed as significant.

The treatment resulted in highly significant reductions over Base level for AST and ALT and an increase for the AST/ALT ratio. The reduction in blood aminotransferases is unexpected. These tests are designed to detect elevated values as an indicator of liver damage. However, it is not clear whether a reduction in these enzyme levels is an indicator of “improved” liver health. This aspect of the study requires further specific trial work.

The fact that significant results were obtained using all 32 data points but not with the 11 data points in each period, is possibly due to nothing other than sample size. However, it does point out that the reductions in Blood Lipid values occur fairly quickly following Nanocosanol treatment, with on-going reductions proceeding very slowly, if at all.

The most important result is the demonstration that decreases in both Blood Lipid and Blood Liver values are a function of the Base level. These results suggest that Nanocosanol will have very little effect on subjects with low to normal blood values. However for those subjects in the population with elevated values, Nanocosanol could have the potential to bring about 15-20% reductions in a very short time.

The positive side effects mentioned effects included a reduction in gastrointestinal esophageal reflux disease (GERD) symptoms (reported by 3 subjects) and reduction of irritable bowel syndrome symptoms was reported by one volunteer. Seven (64%) of the volunteers reported an increase in the number of bowl movements without a significant stool softening. In some cases the number of bowl movements increased twofold without any negative impacts. At each blood draw each volunteer was asked to fill out a report about any negative or positive side effects. Over half of the trial participants reported positive health impacts while zero negative side effects were reported.

Typically, the manifestation and improvements in irritable bowel syndrome could include not only a reduction in the number of bowel movements per day when those bowel movements are excessive, but also an increase in weekly bowel movements when the weekly bowel movements are minimal, such as only two or three bowel movements per week. Although the exact mechanism for the dietary or brain-gut response is not completely known, the results have been positive.

As to GERD, in some cases, it is typically caused by a failure of the cardia or minimal stomach acid. The method using the composition effectively counteracts such causes in some of the sampled subjects as noted above.

Many modifications and other embodiments of the invention will come to the mind of one skilled in the art having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is understood that the invention is not to be limited to the specific embodiments disclosed, and that modifications and embodiments are intended to be included within the scope of the appended claims. 

1. A method of manufacturing a human or animal dietary supplement composition effective for enhancing gastrointestinal motility in humans and other animals comprising a blood lipid health-effective amount of one or more long chain (C24- C36) primary alcohols comprising policosanols dispersed in food-grade fats or oils, comprising: dissolving policosonal containing rice bran wax extract into a mixture of cranberry and amaranth seed oily extracts at a temperature above ambient temperature; cooling to ambient temperature; adding soybean lecithin; and homogenizing the resultant mixture.
 2. The method according to claim 1, wherein the particle sizes of the alcohols are less than 10 microns and greater than 2 microns.
 3. The method according to claim 2, wherein the particle sizes of the alcohols are greater than 2.0 microns and less than 5.0 microns.
 4. The method according to claim 1, further comprising dissolving the policosonal at around 65 degrees C.
 5. The method according to claim 1, further comprising encapsulating the mixture within gelatin softgels.
 6. The method according to claim 1, wherein the food grade fats and oils comprise: not less than twenty five (25%) by weight of polyunsaturated fatty acids; and not less than ten percent (10%) by weight of omega-3 fatty acids; not less than eight fifty parts per million (850 ppm) by weight of tocopherols and tocotrienols in total.
 7. The method according to claim 1, wherein the policonsanols comprise from about 0.1 percent by weight of the fats or oils to about 6.0 percent by weight of the fats or oils.
 8. The method according to claim 1, wherein the food-grade fats or oils further comprise at least one of fish and marine/algal oils, safflower oil, sunflower seed oil, soybean oil, canola oil, olive oil, linseed oil, flax oil, hemp oil, borage oil, evening primrose oil, chia oil and hibiscus oil.
 9. The method according to claim 1, wherein the policosanols comprise from about 0.5% by weight of the fats or oils to about 5.0% by weight of the fats or oils.
 10. The method according to claim 1, wherein the policosanols comprise from about 1.0% by weight of the fats or oils to about 5.0% by weight of the fats or oils.
 11. The method according to claim 1, further comprising biologically active extracts and compounds, selected from, minerals, carotenoids, tocopherols, tocotrienols, phytosterols, polyphenols, polysaccharides and bioflavonoids.
 12. The method according to claim 1, further comprising a delivery vehicle as an emulsion, solution, dispersion, cream, tablet, capsules and powder.
 13. The method according to claim 1, further comprising a delivery vehicle for carrying the composition comprising food, feed or beverage.
 14. A method of manufacturing a human or animal dietary supplement composition effective for enhancing gastrointestinal motility in humans and other animals comprising a blood lipid health-effective amount of one or more long chain (C24- C36) primary alcohols comprising policosanols dispersed in food-grade fats or oils, comprising: dissolving policosonal containing rice bran wax extract into a mixture of cranberry and amaranth seed oily extracts at a temperature above ambient temperature; cooling to ambient temperature; adding soybean lecithin; and homogenizing the resultant mixture, wherein the particle sizes of the alcohols are greater than 2 microns and less than 10 microns.
 15. The method according to claim 14, and further comprising dissolving the policosonal at around 65 degrees C.
 16. The method according to claim 14, further comprising encapsulating the mixture within gelatin softgels.
 17. The method according to claim 14, wherein the food grade fats and oils comprise: not less than twenty five (25%) by weight of polyunsaturated fatty acids; not less than ten percent (10%) by weight of omega-3 fatty acids; and not less than eight fifty parts per million (850 ppm) by weight of tocopherols and tocotrienols in total.
 18. The method according to claim 14, wherein the policonsanols comprise from about 0.1 percent by weight of the fats or oils to about 6.0 percent by weight of the fats or oils.
 19. The method according to claim 14, wherein the food-grade fats or oils further comprise at least one of fish and marine/algal oils, safflower oil, sunflower seed oil, soybean oil, canola oil, olive oil, linseed oil, flax oil, hemp oil, borage oil, evening primrose oil, chia oil and hibiscus oil.
 20. The method according to claim 14, wherein the policosanols comprise from about 0.5% by weight of the fats or oils to about 5.0% by weight of the fats or oils.
 21. The method according to claim 14, wherein the policosanols comprise from about 1.0% by weight of the fats or oils to about 5.0% by weight of the fats or oils.
 22. The method according to claim 14, further comprising biologically active extracts and compounds, selected from at least one of minerals, carotenoids, tocopherols, tocotrienols, phytosterols, polyphenols, polysaccharides and bioflavonoids.
 23. The method according to claim 14, further comprising a delivery vehicle as an emulsion, solution, dispersion, cream, tablet, capsules and powder.
 24. The method according to claim 14, further comprising a delivery vehicle for carrying the composition comprising food, feed or beverage. 